The transdermal route of parenteral delivery of drugs provides many advantages and transdermal systems for delivering a wide variety of drugs or other beneficial agents are described in U.S. Pat. Nos. 3,598,122, 3,598,123, 4,379,454, 4,286,592, 4,314,557 and 4,568,343 for example, all of which are incorporated herein by reference. In many cases, drugs which would appear to be ideal candidates for transdermal delivery are found to have such low permeability through intact skin that they cannot be delivered at therapeutically effective rates from reasonably sized systems.
In an effort to increase skin permeability so that drugs can be delivered at therapeutically effective rates, it has been proposed to pretreat the skin with various chemicals or to concurrently deliver the drug in the presence of a permeation enhancer. Various materials have been suggested for this purpose as described in U.S. Pat. Nos. 4,299,826, 4,343,798, 4,046,886, 4,130,643, 4,405,616, 4,335,115, 4,130,667, 3,903,256, 4,379,454, 3,527,864, 3,952,099, 3,896,238, 3,472,931 which are incorporated herein by reference, British Pat. No. 1,001,949 and Idson, Percutaneous Absorption, J. Phar. Sci., Vol.64, No. b6, June 1975, pp. 901-924 (particularly 919-921).
To be considered useful, a permeation enhancer should have the ability to enhance the permeability of the skin for at least one and preferably a significant number of drugs. More importantly, it should be able to enhance the skin permeability such that the drug delivery rate from a reasonably sized system (preferably 5-50 cm.sup.2), is at therapeutic levels. Additionally, the enhancer, when applied to the skin surface from a controlled drug delivery system, should be non-toxic, non-irritating on prolonged exposure and under occlusion, and non-sensitizing on repeated exposure. Preferably it should also be odorless and capable of delivering drugs without producing burning or tingling sensations.
It is often difficult to predict which enhancers will work for which drugs. In systemic drug delivery applications, a compound that enhances the permeability of one drug or a family of drugs may not necessarily enhance the permeability of another. Therefore, the usefulness of a particular compound must be analyzed on a drug by drug basis.
According to our invention, we have discovered that glycerol monooleate (GMO), is effective in enhancing the permeation of steroids, nitrates and biperiden, through body surfaces and membranes generally, and through skin in particular, and when formulated in pharmaceutical compositions with other materials appears to satisfy the criteria noted above. Most importantly, glycerol monooleate is able to enhance the permeability of these drugs such that therapeutic delivery rates can be attained with reasonably sized systems.
It is accordingly an object of our invention to increase the permeability of body surfaces of animals and humans, including the mucosa and other membranes and more particularly of human skin, for the systemic delivery of particular drugs by the concurrent application of the drug and GMO to the body surface.
It is another object of our invention to provide examples of compositions of matter for application to the skin which comprise GMO and one or more drugs, specifically steroids, alone or in combinations, nitrates or biperiden.
These and other objects and advantages will be readily apparent from the following description with reference to the accompanying drawings wherein a composition of matter is applied to a body surface or membrane to deliver at least one drug, at a therapeutically effective rate, by permeation through a body surface or membrane comprising, in combination: at least one drug selected from the group consisting of steroids, nitrates and biperiden and a permeation enhancing amount of glycerol monooleate.